Fentanyl is a potent narcotic analgesic with pharmacological effects similar to morphine. Fentanyl is 50 to 100 times more potent than morphine on a weight basis. Fentanyl is a mu-receptor agonist acting on receptors distributed in the brain, spinal cord and other tissues. Opioids produce both analgesia and sedation. Opiate agonists appear to prevent the release of beta-endorphin, possibly by altering the patients perceived level of pain and anxiety, although the presence of pain may still be recognised (1).
Parenteral fentanyl is indicated for anaesthesia, treating postoperative pain, and as a premedicant. Transdermal fentanyl is used for managing chronic pain in patients requiring opioids. Fentanyl lozenge/sucker (Oralet®) is indicated to induce anxiolysis and analgesia prior to surgery in pediatric and adult patients. Oral transmucosal fentanyl (Actiq®) is indicated for the management of breakthrough cancer pain in adults with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Fentanyl Oralet® is only indicated for use in a hospital setting as an anaesthetic pre-medication in the operating room setting or to induce conscious sedation prior to a diagnostic or therapeutic procedure in other monitored anaesthesia care settings in the hospital.
In normal doses, the most common side-effects of morphine and other opioid analgesics are nausea, vomiting, constipation, drowsiness, and confusion. Tolerance generally develops with long-term use. Micturition may be difficult and there may be ureteric or biliary spasm; there is also an antidiuretic effect. Dry mouth, sweating, facial flushing, vertigo, bradycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, changes of mood, hallucinations, and miosis also occur. These effects tend to occur more commonly in ambulant patients than in those at rest in bed and in those without severe pain. Raised intracranial pressure occurs in some patients. Muscle rigidity has been reported following high doses. The euphoric activity of morphine and similar compounds has led to their abuse.
Unlike morphine, fentanyl is reported not to cause significant histamine release. Transient hypotension may follow intravenous administration. Muscle rigidity in high doses may occur and may require administration of muscle relaxants; caution is advised in patients with myasthenia gravis.
It has been shown (4-7) that fentanyl administered intranasally in doses of 0.027 mg every 5 minutes, as necessary, is effective in the relief of postoperative pain and cancer pain. In this trial the drug was delivered in small dilute doses of small amounts of agent at a predetermined interval of 5 minutes.
Intranasal delivery of low concentrations and low doses of fentanyl has been performed. Concentrations and doses have been maintained low due to the risk of respiratory depression associated with high doses. Demand-adapted titration was considered to be the only method of avoiding the risk of side effects (4-7). Thus, repeated delivery of a composition of ca. 50 μg/mL of fentanyl was administered.
Animal data (rabbits) showed rapid occurring absorption by use of the nasal route. The nasal route would therefore be suitable for use in patients requiring rapid relief of severe pain. General advantages of nasal application aiming at systemic effect are ease of self-administration, supporting a health-economic argument and the self-care concept. In addition, first pass liver metabolism and gastro-intestinal metabolism is avoided.
Intravenously, doses of 50 to 150 μg/kg are indicated for anaesthesia in cardiac surgery whereas doses of 50 to 100 μg IM are effective as a pre-medication and adjunct to regional anaesthesia. Continuous intravenous infusion of fentanyl 1.5 μg/kg/hour for 24 hours has been effective in providing postoperative analgesia without significant respiratory depression in patients who underwent hysterectomy.
Transdermal doses range from 25 to 100 μg/hr. Initial doses not exceeding 25 μg/hr are recommended (1).
Oral transmucosal fentanyl citrate is marketed as fentanyl Oralet® and Actiq®. fentanyl lozenge/sucker (fentanyl Oralet®) in doses of 5 to 15 μg/kg (maximum 400 μg) is indicated to induce anxiolysis and analgesia prior to surgery for pediatric patients. Adult dosing of fentanyl Oralet® is 5 μg/kg, with a maximum dose of 400 μg. Doses of Actiq® for opioid tolerant patients with breakthrough cancer pain range from 200 to 1600 μg. The initial adult dose of Actiq® is 200 μg. From this initial dose, patients should be closely followed and the dosage not changed until the patient reaches a dose that provides adequate analgesia using a single Actiq® dosage unit per break-through cancer pain episode.
The administration of 3 mL of fentanyl citrate 500 μg/mL (318 μg/mL fentanyl base) via nebulization was effective in providing postoperative analgesia in 10 patients who underwent a variety of surgical procedures. However, duration of analgesia varied considerably from 5 to 90 minutes. This route of administration is inefficient and labour intensive and therefore is generally not recommended (1).
Fentanyl produces analgesia almost immediately following intravenous administration whereas in lozenge/sucker delivery and oral transmucosal administration, onset is seen within 15 minutes.
Fentanyl is metabolised in the liver and excreted in the urine primarily as metabolites (less than 7% unchanged drug). The half-life of fentanyl is 2 to 4 hours. Fentanyl has a distribution half-life of 10 minutes in adults and children (1).